Successful use of ketamine to treat severe depression with suicidality post-COVID-19 – A case report

Every second patient who suffers from COVID-19 experiences is at risk for depression. The treatment of severe depression with suicidal risk is challenging in patients with COVID-19 given the restrictions in access to and safety concerns with the use of electroconvulsive therapy during the COVID pandemic. Although ketamine is effective in treating depression, especially in presence of acute suicidality, to date, there are no reports on ketamine use to treat severe depression in the context of COVID-19. In this case report, we describe the success of ketamine to treat a person with severe depression and suicidality following COVID-19 infection.


Introduction
One in two patients with COVID-19 suffers from depressive symptoms ( Deng et al., 2021 ). Treating severe depression with suicidal ideas could be challenging in patients with COVID-19. Electroconvulsive therapy [ECT] administration during the COVID-19 pandemic is associated with risks of aerosolization of the COVID-19 virus and subsequent crosstransmission to other patients and healthcare providers. The ECT services need to be revamped to ensure adequate prior screening in all patients for COVID-19, the use of adequate personalized protective equipment by the healthcare providers administering the ECT, effective triaging of the cases, use of separate sterilized equipment in the Bain circuit, with standardized sterilization after every session ( Sienaert et al., 2020 ;Tor et al., 2020 ). Despite this, the entire process can pose significantly elevated risks of aerosolization of secretions and cross-transmission of COVID-19. As electroconvulsive therapy during the COVID pandemic is risky, one has to consider other treatment options for those with suicidal ideas. Ketamine is effective in treating depression, especially in the context of acute suicidality. However, to date, there are no reports on ketamine use to treat severe depression in the context of COVID-19. In this case report, we describe the success of ketamine in treating a person with severe depression and suicidality following COVID-19 infection.

Case description
A 40-year-old married male presented to the emergency care of a tertiary care hospital with a one-week history of pervasive low mood, anhedonia, easy fatiguability, reduced self-esteem, and avoidance of work be-cause of concentration difficulty. He felt a sense of unworthiness, ideas of hopelessness and helplessness. He tried to end his life by suicide of high intentionality and lethality from consuming 20 tablets of Tab Clonazepam 0.5 mg when he was alone in his apartment. Subsequently, he was admitted to the Intensive care unit, and on examination, he had depressed affect, depressive cognitions, active suicidal ideation and expressed no remorse for the DSH attempt. The Beck's Suicide Intent Scale ( Beck et al., 1961 ) revealed high intent with a score of 35.
Two weeks before the presentation, he experienced fever, cough, and breathlessness for three days which progressed to hypoxia [Sp02 of 90%]. A reverse-transcriptase polymerase chain reaction test of his throat swab for SARS-CoV2 was positive. A computed tomogram of the chest revealed the severity of 10/25 ( Chang et al., 2005 ), and the COVID-19 Reporting and Data System [CORADS] score was 6 ( Prokop et al., 2020 ). He had elevated inflammatory markers (Lactate Dehydrogenase 313 IU/L, Serum Ferritin 1288 ng/ml, C-Reactive Protein-37.94 mg/l, D-dimer-125ng/ml) and deranged liver enzymes (Aspartate Transaminase of 191 IU/L, Alanine Transaminase 75 IU/L). He was diagnosed with moderate COVID-19 infection and treated with Inj. Dexamethasone 6mg/day, Inj Enoxaparin 40 mg/day, Nebulization with Salbutamol 5 mg and Budesonide 500 mcg thrice daily for the next six days. The hypoxia was controlled with low-flow humidified oxygenation using a face mask for the initial three days of hospitalization. Ten days after admission, the patient showed significant improvement in symptoms and was discharged after persistence of recovery.
He had interpersonal issues with his wife and stayed separated from his wife and daughter for the preceeding five years. During this period, he had a non-pervasive sad mood without any social or occupational  75% reduction as compared to baseline] * MADRS-Montgomery-Asberg Depression Rating Scale ˆ scores was recorded following an interpersonal stressor between patient and family.A comparison of the scores from baseline to end of day 5 revealed that there was a 93.75% improvement in depressive symptoms.
dysfunction previous to the current depressive episode. After a detailed evaluation, he was diagnosed with a severe depressive episode without psychotic symptoms as per the International Classification of Diseases ( Organization, 1992 ).
His biochemical investigations, including thyroid function test, liver function tests and renal function tests, were normal. He was started on Tab. Venlafaxine 75mg/day and increased to 150mg/ day. After a week of treatment, the patient continued to have active suicidal ideation with no considerable improvement in his depressive symptoms. The recent COVID infection and compromised pulmonary function were a concern for electroconvulsive therapy. Hence, we considered intravenous infusion of ketamine after a discussion with the patient and his family. The patient received ketamine infusions on alternate days. We administered 0.5mg/kg of ketamine over 40 min at the rate of 75ml/hr as per the previous study protocols ( Xu et al., 2016 ). Rapid response was seen after ketamine administration which was greater one hour post-administration than after four hours. The patient showed considerable improvement in his depressive symptoms and suicidal ideas over the course of treatment. The Montgomery Asberg Depression Rating scale ( Montgomery and Åsberg, 1979 ) score decreased from thirty-two at baseline to two at the end of five sessions. Columbia Suicide Severity Rating scale ( Posner et al., 2011 ) was applied serially, and the intensity of the ideation was 22 at the baseline. After the 4 th cycle of Ketamine infusion, there was no suicidal ideation noted. The details are given in supplement 1.
The patient reported nausea during the first two sessions that were symptomatically treated. No serious adverse events or dissociative experiences were observed. The details of the clinical depression severity and improvement as measured on the Montgomery Asberg Depression Rating scale ( Montgomery and Åsberg, 1979 ); is mentioned in Table 1 . He was discharged subsequently and maintained improvement during follow-up visit at one month post-discharge.

Discussion
To the best of our knowledge, this is the first report to describe the successful use of ketamine in treating severe depression with suicidal ideas after COVID-19 infection. The index patient presented with severe depression with suicidal risk following COVID-19 and improved with five sessions of ketamine infusion. Ketamine infusion was well tolerated with minimal side effects. Ketamine is a safe alternative to ECT in comorbid COVID-19, considering the concerns associated with ECT during the pandemic.
Mental health issues following COVID -19 are multifactorial; in addition to the secondary psychological reaction to being infected by a novel, potentially lethal virus during the pandemic, other factors such as immune dysregulation, pro-coagulant state, and medication side effects are also proposed. In the index patient, we could not identify any additional proximal psychosocial stress for the recent episode of depression and considered the post-covid state as the possible reason. Ketamine has shown rapid improvement as early as two hours in patients with MDD, especially in cases with high risk of suicide or past history of suicide attempts ( Corriger and Pickering, 2019 ). Several other studies have reported robust and rapid improvement in depressive symptoms with ketamine ( Dean et al., 2021 ;Marcantoni et al., 2020 ). A recent meta-analysis that analyzed data from 572 adult participants from 15 independent RCTs has reported the beneficial effects of a single infusion of ketamine in reducing suicidality for up to 72 hours ( Witt et al., 2020 ). In addition to the measurement of acute response, the metaanalysis recommended more ecological momentary assessments to map the immediate and intermediate response. Brain-derived neurotrophic [BDNF] is an important mediator of neural plasticity and is associated with anti-depressant effects. Administration of ketamine can lead to a rise in pro-BDNF and BDNF levels in an AMPA receptor-dependent manner, explaining the immediate efficacy of ketamine in reducing suicidality and improving depression ( Nguyen et al., 2016 ). Although ketamine nasal spray is approved for treatment-resistant depression in adults ( FDA, 2020 ), we administered ketamine as an infusion due to the non-availability of esketamine in India. In addition to its antidepressant effect, ketamine has bronchodilator properties ( Lau and Zed, 2001 ) and immunomodulatory effects ( Loix et al., 2011 ) beneficial in persons with COVID-19. Recently its use has been supported as an induction agent for anaesthesia in patients with Covid-19 ( Cook et al., 2020 ).
The use of ECT in the recovery phase of COVID-19 prompted concerns about the anaesthesia given the recent viral infection and compromised pulmonary function. ECT services worldwide face a scarcity of anaesthesiologists, and resources either have been shut down completely or received a massive hit being considered an elective-procedure alongside the obvious risk of transmission of COVID-19. ECT under anaesthesia is an aerosol-generating procedure lasting for hours which demands close contact with the patient in a confined environment. The ECT team comprises of professionals from multiple disciplines which further increases the risk of cross-infection. ECT is frequently considered in the geriatric population who tend to have more comorbidities, thus increasing the risk of a severe infection. Thus, ketamine can be a feasible and safe alternative to ECT in comorbid COVID-19 ( Tor et al., 2020 ).
Depression is common psychiatry comorbidity following cerebrovascular accidents. Post-stroke depression is associated with subcortical pathology, vascular changes, and a poor response to conventional treatment ( Robinson and Jorge, 2016 ). COVID-19 is associated with an increased risk for stroke, mediated mainly through hypercoagulability, endothelial dysfunction, and immune mechanisms ( Small et al., 2022 ). Given that ketamine is promising in animal models of post-stroke depression ( Xiong et al., 2020 ;Zhang et al., 2021 ), we hypothesize that the use of ketamine may have special significance in the treatment of depression with comorbid COVID-19 infection.
In our case, the response was noted to be temporally correlated with ketamine infusion. There are two limitations to our case report. Firstly, it is probable that the improvement in the depression scores could have been in part mediated by the effects of venlafaxine ( Ellingrod and Perry, 1994 ). Second, is the caveat that all patients given ketamine infusion may not respond to the treatment. In this case, the patient responded well to ketamine. As this is an anecdotal case report, larger studies examining the effectiveness of ketamine in depression with COVID-19 are required. To conclude, this case report demonstrates the safe and successful use of ketamine infusion in the treatment of severe depression with suicidal risk in the context of COVID-19. Considering the associated advantages as described, one could consider ketamine treatment before ECT in persons with COVID-19.

Ethics
As this manuscript contains a case report, prior ethical clearance is not needed as per the Institute ethics committee guidelines.

Declaration of patient consent
The authors certify that they have obtained the appropriate prior informed written patient consent form in line with the Declaration of Helsinki. The patient has given his consent for his clinical information to be reported in the journal. The patient understands that anonymity will be maintained and no personally identifiable information shall be revealed through the case report.

Data availability statement
The data that support the findings of this study are available from the corresponding author upon request.